Mechanisms of inhibition of human monoclonal antibodies in immune thrombotic thrombocytopenic purpura (2023)

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Available online from April 11, 2023

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Binding of an antibody to a plasma metalloprotease ADAMTS13 is required for the development of immune thrombotic thrombocytopenic purpura (iTTP). Inhibition of ADAMTS13-mediated VWF cleavage by such antibodies clearly plays a role in the pathophysiology of the disease, although the mechanisms by which they inhibit ADAMTS13 enzymatic function are not fully understood. At least some immunoglobulin G-type antibodies appear to affect the conformational accessibility of the ADAMTS13 domains involved in substrate recognition and inhibitory antibody binding. We used single variable region chain fragments (scFvs) previously identified by phage display from patients with iTTP to study the mechanisms of action of inhibitory human monoclonal antibodies. Using full-length recombinant ADAMTS13, truncated ADAMTS13 variants, and native ADAMTS13 in normal human plasma, we found that all three inhibitory monoclonal antibodies affect the rate of enzyme turnover much more than von Willebrand factor (VWF). . Hydrogen-deuterium exchange and mass spectrometry (HX-MS) experiments with each of these inhibitory antibodies revealed that residues in the active site of the ADAMTS13 catalytic domain are differentially exposed to solvent in the presence and absence of monoclonal antibody binding. These results support the hypothesis that inhibition of ADAMTS13 in iTTP is not necessarily due to antibodies preventing direct binding of VWF, but rather is due to allosteric effects that prevent VWF cleavage, likely through conformation of the catalytic center in the protease domain of ADAMTS13 to affect it. Our results provide new insights into the mechanism of autoantibody-mediated inhibition of ADAMTS13 and the pathogenesis of iTTP.

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© 2023 of the American Society of Hematology


What antibodies are in thrombotic thrombocytopenic purpura? ›

This form or TTP is considered to be an autoimmune disease and is caused when patients develop an antibody against the ADAMTS13 protease leading to low levels of the protease. If the disorder is present at birth (familial form), signs and symptoms may typically appear earlier, in infancy or early childhood.

How do ADAMTS13 and vwf interact? ›

Proteolysis of VWF by ADAMTS13.

In its globular conformation, the A3 domain collagen binding site is exposed. ADAMTS13 can bind to this globular VWF via its TSP (5-8) and CUB domains (C), step 1. This enables VWF and ADAMTS13 complexes to form and circulate in plasma.

Is TTP intravascular hemolysis? ›

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia classically characterized by the pentad of fever, hemolytic anemia, thrombocytopenia, and renal and neurologic dysfunction.

What causes TTP blood disorder? ›

The cause of TTP is often unknown, but some people develop it after taking certain drugs (including quinine, cyclosporine, and mitomycin C), after certain types of intestinal infection, during pregnancy, or rarely as an inherited disease. In most people, TTP is an autoimmune disorder.

What is the mechanism of action of TTP? ›

The underlying mechanism typically involves antibodies inhibiting the enzyme ADAMTS13. This results in decreased break down of large multimers of von Willebrand factor (vWF) into smaller units. Less commonly TTP is inherited, known as Upshaw–Schulman syndrome, such that ADAMTS13 dysfunction is present from birth.

What is the immune response to ITP? ›

In ITP, the immune system is stimulated to attack your body's own platelets. Most often this is a result of antibody production against platelets. In a small number of cases, a type of white blood cell called T-cells will directly attack platelets.

What is the mechanism of action of ADAMTS13? ›

The ADAMTS13 enzyme processes a large protein called von Willebrand factor. This protein is involved in the first step of blood clotting at the site of injury, which is to help cells called platelets stick together and attach to the walls of blood vessels, forming temporary clots.

What is the mechanism of VWF ADAMTS13? ›

ADAMTS13 is secreted into plasma as a constitutively active enzyme at a plasma concentration of, approximately, 1 μg/ml [12–14]. It cleaves a large adhesive glycoprotein, von Willebrand factor (VWF), that plays an essential role in primary hemostasis by recruiting platelets to the site of vessel injury [15].

Is ADAMTS13 a VWF cleaving protease? ›

The congenital or acquired deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS-13 has been specifically associated with a diagnosis of thrombotic thrombocytopenic purpura (TTP), a microangiopathy characterized by the formation of occlusive platelet thrombi.

What enzyme is mainly affected in TTP? ›

What causes TTP? TTP occurs when you do not have the right amount of an enzyme (a type of protein in your blood) called ADAMTS13. This enzyme controls how your blood clots. If you do not have enough ADAMTS13, your body makes too many blood clots.

Why does TTP cause hemolysis? ›

Pathophysiology of TTP

Loose strands of platelets and fibrin are deposited in multiple small vessels and damage passing platelets and red blood cells (RBCs), causing significant thrombocytopenia and anemia (microangiopathic hemolytic anemia).

Is TTP immune mediated? ›

TTP is divided into congenital (inherited) and immune-mediated (acquired) TTP. Congenital TTP (also called Upshaw–Schulman syndrome) is caused by biallelic mutations in the ADAMTS13 gene [8]. Immune-mediated TTP (iTTP) is an autoimmune disorder resulting from the production of autoantibodies against ADAMTS13 [1-3].

Why a deficiency of ADAMTS13 causes clotting because of TTP? ›

A lack of activity in the ADAMTS13 enzyme (a type of protein in the blood) causes thrombotic thrombocytopenic purpura (TTP). The ADAMTS13 gene controls the enzyme, which is involved in blood clotting. Not having enough enzyme activity causes overactive blood clotting.

What causes ADAMTS13 deficiency? ›

ADAMTS13 deficiency can be acquired or congenital

Secondary (23 to 67 percent of cases), arising from a variety of conditions, including autoimmune disorders, solid organ or hematopoietic cell transplant, malignancy, drugs and pregnancy.

What is the most common cause of death in TTP? ›

Cardiovascular disease is a leading cause of death in patients that survive their first episode of TTP.

How does rituximab work for TTP? ›

Rituximab as elective therapy to prevent TTP relapse

Rituximab is used to prevent relapse in patients with a fall in ADAMTS13 activity and symptoms based on the patient's relapse history. The target is normalisation of ADAMTS13 activity as above.

What is the role of steroids in TTP? ›

Corticosteroids. Corticosteroids are used in the acute management of acquired TTP, and should be started upfront together with PEX. Steroids are believed to suppress the production of anti-ADAMTS13 autoantibodies.

What is the primary mechanism of ITP? ›

The pathophysiology of ITP is complex and abnormalities of both the B-cell and the T-cell compartments have been identified. The mechanisms of the thrombocytopenia involve both increased platelet destruction and, in a significant proportion of cases, impaired platelet production.

How does immunoglobulin work in ITP? ›

In patients with ITP, Intravenous immunoglobulin (IVIG) increases the platelet count by decreasing the destruction of platelets in your spleen. IVIG may also work in patients with or without a spleen by binding to and neutralizing the antibodies responsible for destroying platelets.

What antibodies destroy platelets? ›

With ITP, your immune system attacks your body's own platelets by mistake. Most often, this is a result of antibody production against platelets. In a small number of cases, a type of white blood cell called T-cells will directly attack platelets.

Which immunoglobulin is responsible for ITP? ›

In immune thrombocytopenia (ITP), an abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes.

What is an ADAMTS13 inhibitor? ›

ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) is a plasma protein responsible for regulating the interaction of platelets with von Willebrand factor (VWF) and physiologic proteolytic cleavage of ultra large (UL) VWF multimers at the Tyr(1605)- Met(1606) bond in the A2 domain ...

What is the ADAMTS13 level in TTP? ›

An ADAMTS13 activity level of less than 10% supports the diagnosis of TTP in appropriate clinical contexts, but many centers do not offer testing in-house and must send out the test to a reference laboratory with a turnaround time of several days.

What is the mechanism of action of rituximab in ITP? ›

The mechanism of action of rituximab in ITP is assumed to be due to selective depletion of CD20+ B cells, which affects autoantibody development.

What is the role of ADAMTS13 in hemostasis? ›

ADAMTS13 cleaves the polymeric force-sensor von Willebrand factor (VWF) that unfolds under shear stress and recruits platelets to sites of vascular injury. Shear force–dependent cleavage at a single Tyr–Met peptide bond in the unfolded VWF A2 domain serves to reduce the size of VWF polymers in circulation.

What is the role of VWF and fibrinogen in platelet function? ›

It has been demonstrated that von Willebrand factor (VWF) and fibrinogen (Fg) are two essential molecules that mediate platelet adhesion and aggregation [1]. Deficiencies in either of these molecules are associated with bleeding disorders [i.e. von Willebrand disease (VWD) and afibrinogenemia].

What is the difference between TTP and ITP? ›

ITP is an autiommune disorder in which the body destroys its own platelets. TTP can occur if you do not have the right amount of an enzyme that controls how your blood clots.

Does VWF bind directly to platelets? ›

VWF binds to collagen and then tethers platelets to the collagen surface through interaction with platelet glycoprotein Ib and also contributes to the thrombus formation on the collagen surface.

What receptor does VWF bind on platelets? ›

The adhesion molecule von Willebrand factor (vWF) activates platelets upon binding 2 surface receptors, glycoprotein (GP) Ib-V-IX and integrin IIbβ3.

What does von Willebrand factor bind to? ›

VWF has a central role in primary haemostasis where it mediates platelet adhesion to damaged vascular subendothelium and subsequently platelet aggregation. Following a vascular injury, VWF binds specifically to fibrillar collagen type I and III.

Why is fibrinogen normal in TTP? ›

D-dimer and fibrinogen assay findings are as follows: D-dimers are indicative of fibrinolysis and thus, thrombin activation, which usually is normal or mildly elevated in patients with TTP. Fibrinogen typically is in the high to high-normal range.

Is ADAMTS13 low in TTP? ›

Prognostic Value of ADAMTS13 Testing in TTP

Patients with inherited TTP usually have very low plasma levels of ADAMTS13, both during acute disease and during disease-free periods.

Why does LDH increase in TTP? ›

Elevated serum lactate dehydrogenase (LDH) is a characteristic finding in patients with thrombotic thrombocytopenic purpura (TTP). It is widely accepted that total serum LDH principally rises due to the release of red blood cell LDH as a consequence of intravascular hemolysis.

What is the pathogenesis of thrombocytopenic purpura? ›

The pathogenesis of ITP remains unclear although both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells, cytokine imbalances, and the contribution of the bone marrow niche have now been recognized to be important.

Can you have TTP without hemolysis? ›

In these cases, the absence of thrombocytopenia and hemolytic anemia can be explained by an early stage of TTP when platelet aggregation and thrombosis are not yet diffuse. Indeed, schistocytes are initially absent in up to 30% of patients, and blood smear examination should be regularly repeated.

What are immune mediated causes of thrombocytopenia? ›

Immune thrombocytopenia usually happens when your immune system mistakenly attacks and destroys platelets, which are cell fragments that help blood clot. In adults, this may be triggered by infection with HIV , hepatitis or H. pylori — the type of bacteria that causes stomach ulcers.

What protein is used to diagnose TTP? ›

By drawing a small amount of blood from your arm, the OSUCCC – James experts can analyze the sample to determine if the ADAMTS13 enzyme (a protein in the blood) is active. Most cases of TTP are caused by a problem with this enzyme.

What happens in ADAMTS13 deficiency? ›

In humans, genetic or acquired deficiency in ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP), a condition characterized by thrombocytopenia and hemolytic anemia with microvascular platelet thrombi.

What is inherited TTP usually a deficiency of? ›

TTP is specifically related to a severe deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the specific von Willebrand factor-cleaving protease.

Which disease is associated with an increased risk for developing TTP? ›

Other risk factors that can trigger TTP include: Diseases and conditions such as cancer, HIV, lupus, infections and pregnancy. Some medical procedures such as surgery and blood- and marrow-stem cell transplant.

What is the most common antibody found in post transfusion purpura? ›

Post-transfusion purpura (PTP) is a rare yet serious disease characterized by severe thrombocytopenia occurring after a blood transfusion. It is caused by alloimmunization against platelet antigens, anti-HPA-1a being the most frequent antibody.

What is the gold standard test for TTP? ›

Coombs Test

This test can tell whether TTP is causing anemia by determining if certain proteins are destroying red blood cells. If the test is negative, TTP is the cause.

Which autoantibody is associated with thrombosis fetal loss and thrombocytopenia? ›

Antiphospholipid syndrome (APS) is an autoimmune disorder that is associated with pregnancy complications, including preeclampsia, thrombosis, autoimmune thrombocytopenia, fetal growth restriction, and fetal loss.

Which test is diagnostic for thrombotic thrombocytopenic purpura? ›

Diagnostic tests used to confirm thrombotic thrombocytopenic purpura may include: Complete blood count (CBC). A CBC measures the number of platelets as well as the number of red blood cells and white blood cells. People with TTP have a lower number of red blood cells and platelets.

How is immune thrombocytopenic purpura treated with IVIG? ›

Intravenous immune globulin (IVIG) is a treatment for immune thrombocytopenia (ITP). IVIG is given by IV infusion over several hours. IVIG works to slow down the destruction of platelets. Your child will get medicine such as Tylenol® or Benadryl® to help with side effects.

What is the mechanism of post transfusion purpura? ›

Post-transfusion purpura is a rare transfusion-related complication that often goes undiagnosed. It is due to alloimmunization against platelet antigens which leads to acute profound thrombocytopenia following the transfusion of any platelet-containing product (red blood cells or platelets).

What is the difference between ITP and post transfusion purpura? ›

The main distinctions between PTP and ITP are the sudden development of severe thrombocytopenia in the days after transfusion in the former, as well as the presence of platelet-specific antibodies in PTP and broadly reactive or no antibodies in ITP.

How do you confirm diagnosis of TTP? ›

Diagnostic laboratory testing including an ADAMTS13 activity assay, ADAMTS13 functional inhibitor assay, and anti-ADAMTS13 antibody assay may be useful, both as a means of distinguishing TTP from other TMAs and as a means of differentiating iTTP from cTTP.

How can you tell the difference between DIC and TTP? ›

TTP-HUS and DIC can usually be distinguished on the basis of their occurrence in different clinical settings (ie, trauma or sepsis for DIC and fever associated with thrombocytopenia and a microangiopathic hemolytic anemia for TTP-HUS).

What is included in laboratory manifestation of TTP? ›

Laboratory studies for suspected TTP include a CBC, platelet count, blood smears, coagulation studies, BUN creatinine, and serum bilirubin and lactate dehydrogenase.

What autoimmune disorders are associated with thrombocytopenia? ›

Immune thrombocytopenic purpura (ITP) is a rare autoimmune disorder, in which a person's blood doesn't clot properly, because the immune system destroys the blood-clotting platelets. The cause of ITP is not known, but it is due to an immune system error that may be triggered by viral infections.

Which antithrombotic drug is most likely to cause thrombocytopenia? ›

Glycoprotein IIb/IIIa receptor antagonists, a class of antithrombotic drugs, are a common cause of DIT and can induce life-threatening thrombocytopenia.

What are the 3 antiphospholipid antibodies? ›

The three known APLA are: Anticardiolipin antibodies IgG or IgM (ELISA) Anti-beta-2-glycoprotein-I antibodies IgG or IgM (ELISA) Lupus anticoagulants (Functional assays)

Is thrombotic thrombocytopenic purpura the same as ITP? ›

Immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP) are two separate diseases that are characterized by low platelets.


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